Process and intermediates for preparing rauwolscine and derivatives



Patented Oct. 8, 1957 United States Patent ICC PROCESS AND INTERMEDIATESFOR PREPARING N RAUWOLSCINE AND DERIVATIVES Harold Balding MacPhillarny,Madison, N. J assignor to Ciba Pharmaceutical Products, Inc., Summit, N.J., a corporation of New Jersey No Drawing. Application January 13,1955, E000- Serial No. 481,719

18 Claims. (Cl. 260-286) Iv This invention relates to a new process forthe preparation of rauwolscine, also called a-yohirnbine, an alkaloid ofRaztwolfia cancscens [see Mookerjee, J. Ind. Chem. Soc. 18, 33 (1941)]and embraces also the intermediates used in the process of theinvention. N N

Rauwolscine is an indoI-alkaloid and has a carbo- 20 H methoxy group anda free hydroxyl group; it can be represented by the most probableformula:

N N in H I In the above formulae R represents the residue of an alcohol,R stands for R or hydrogen and Hal represents a halogen atom, especiallybromine or iodine. CH 000 As starting materials there are usedadvantageously alkyl deserpidates, such as methyl deserpidate. which canI be obtained according to copending application Serial No. 471,519,filed November 26, 1954, of Paul R. Ulshafer,

More particularly the invention relates to the process by degradation ofthe alkaloid deserpidine to dcserpidic of converting alcohol esters ofdeserpidic acid (11), a acid and subsequent esterification. Deserpidinemay be degradation product of the alkaloid deserpidine, into obtainedaccording to copending application Serial No. rauwolscine. This processcomprises replacing the free 468,161, filed November 10, 1954, of PaulR. Ulshafer. hydroxyl group present in said esters by a halogen atom,The replacement of the free hydroxyl group by a halogen especiallybromine or iodine, if desired hydrolyzing the atom can be accomplisheddirectly or preferably step-wise. estcriiicd carboxyl group, reductivelyremoving the halo- Thus, the free hydroxyl group of the startingmaterial gen atom of the halogeno-desoxydeserpidic acid or its y befirst COflVefted into a y y group @Stfifififid esters (111),respectively thus obtained so as to form With an Organic Suifoilic acid,y y y, P desoxydeserpidic acid or esters (IV) thereof, followed erabiyp-ioiufine SUIiOIIYiOXY group, which y be by hydrolysis f any esterifiedcarboxyl group d i lried out by reaction with the corresponding sulfonylchlotaneously r subsequently f th methoxyl group f h rides as describedin the above mentioned copending apdesoxydeserpidic acid or estersthereof (IV) and re-esteri- Piicalion Serial 471,519; the silifonyioxy Pcan fication of the free carboxyl group of the rauwolscinic b6 replacedy reading the Compound With a metai acid (V) M k j J, I d, Ch S 18 33halide, such as an alkali halide, for example, sodium, (1941) b i d to acarbomethoxy group so as to f r potassium or lithium bromide or iodide.This reaction rauwolscine (I), Th sequence f reactions can ha ispreferably carried out in an inert diluent, such as aceschematicallyindicated as follows, the formulae being the toniil'iie- The Optionalhydrolysis of estfilificd most probable for the compounds set forth.boxy] group at this 5mge 0f the Process y Preferably be carried out bytreatment with alkaline hydrolyzing q agents, such as aqueous alcoholicsolutions of alkali hydroxides. N The reductive removal of the halogenis carried out by g means of hydrogen in statu nascendi or catalyticallyactivated hydrogen under such conditions that the free or esterifiedcarboxyl group and the ring double bonds are not reduced, for exampleusing zinc in the presence of acetic acid or hydrogen activated by Raneynickel. If the carboxyl group of the compounds obtained is esterified itmay be hydrolyzed, for example by the above mentioned means or togetherwith the hydrolysis of the methoxy group which is accomplished byether-splitting hydrolyzing agents, advantageously under acidconditions, for example, by treatment with concentrated hydrobromicROOC- OH R'OOC- Hal ACE: CHa

or hydriodic acid. The final csterification of the rauwolscinic acid iseffected by conventional means, for example by treatment with anesterifying agent capable of transforming a carboxyl group into acarhomethoxy group. especially diazomethane.

The invention extends also to those modifications of the process whereinthe compounds are used and/or obtained in the form of their salts and/orwherein a compound obtainable as an intermediate product at any stage ofthe process for the preparation of rauwolscinic acid is used as startingmaterial and the remaining steps are carried out. It also embraces theintermediates in the form of their salts, for example with organic orinorganic acids, such as hydrohalic acids, sulfuric acid, citric acid.ethane sulfonic acid, hydroxyethane sulfonic acid, methyl sulfuric acid,acetic, citric, oxalic or tartaric acid. The free bases may be convertedinto these salts in customary manner, for example by treating them withthe desired acid, Embraced by the invention are also intermediates witha free carboxyl group in the form of their metal salts, such as alkalior alkaline earth metal salts, for example sodium salt, or salts withorganic bases.

Rauwolscine, the final product of the above mentioned process. showspharmacological activity useful in medi cine; thus it acts as acardiovascular depressant and an antagonist of adrenalin. Furthermore,rauwolscine is a useful intermediate for the preparation of compoundshaving related structure, which may be used as medicaments on account oftheir pharmacological activity. Thus, the free hydroxyl group ofrauwolscine may be converted into the 3.4.S-trimcthoxybenzoyloxy group.to which end rauwolscine may be reacted with 3,4,5-trimethoxybenzoylchloride in pyridine as a solvent; O-3,4,5-trimethoxyhenzoyl rauwolscinehas a hypotensive and adrenolytic activity and can be used as amedicament for this purpose.

The following examples illustrate the invention, the relation betweenparts by Weight and parts by volume being the same as that between thegram and the cubic centimeter and the temperatures being given indegrees centigrade.

Example 1 To a solution of 0.46 part by Weight of methyl deserpidate(dried by distilling toluene from it twice) in 5 parts by volume offreshly distilled pyridine is added dropwise and with cooling 0.46 partby weight of p-toluene-sulfonyl chloride in 1 part by volume of drybenzene. 1 part by volume of pyridine is used to rinse the reagent intothe reaction flask which is securely stoppered and allowed to stand at 5for 5 days. The reddish solution is poured into approximately 50 partsby volume of ice and water. 12 parts by volume of 5 percent aqueousammonia are added and the semi-solid precipitate is triturated for about5 minutes. The mixture is then extracted with three portions ofmethylene chloride of 50 parts by volume, 15 parts by volume and 10parts by volume. The combined methylene chloride extracts are washedthree times with small portions of a cold sodium chloride solution.dried over anhydrous potassium car bonate and evaporated in vacuo to asemi-crystalline residue. 063 part by weight of this is dissolved inmethylene chloride, filtered through approximately 0.02 part by weightof activated charcoal on a cliatomaceous earth filter cell, evaporatedand crystallized from 4 parts by volume of benzene. Additional materialis obtained from the benzene mother liquors. Recrystallization frommethanol gives O-(p-toluenesulfonyl)-rnethyl deserpidate, melting at226-228".

2 parts by weight of p-toluene sulfonyl methyl deserpidate and 2 partsby Weight of sodium iodide are refluxed in 40 parts by volume of dryacetonitrile overnight and then the sodium p-toluene sulfonate formed isfiltered off. The filtrate is evaporated to dryness and the residuetaken up in chloroform and water. The

aqueous phase is extracted three times with chloroform, the combinedchloroform extracts are Washed with water and then evaporated todryness. The residue represents methyl iododesoxydeserpidate; it has theempirical formula C22H2703N2l and can be represented by the mostprobable formula CHaOOC- I I OCH:

It can be converted into iodo-desoxydeserpidic acid by treatment with anaqueous-alcoholic solution of sodium hydroxide.

The methyl i0do-desoxydese1pidate acid is dissolved in glacial aceticacid and 10 parts by weight of zinc dust added in portions while thesolution is refluxed. After refluxing for 18 hours, the reaction mixtureis filtered through filtercel and the residue washed first with glacialacetic acid, then with dilute acetic acid, and finally with Water. Thefiltrate and washings are combined and evaporated almost to dryness. Theresidue is taken up in chloroform and the chloroform solution is washedthree times with water, then with dilute aqueous ammonia and then withwater. The chloroform extract is evaporated to dryness and trituratedwith methanol. Crystals of methyl desoxydeserpidate are obtained whichon recrystallization from methanol melt at 272475"; [a] =-28i1(chloroform). It has the empirical formula CzzHzsOsNz and can berepresented by the probable formula:

CHsOOC- lodo-desoxydeserpidic acid can be dehalogenated in a similarmanner to yield desoxydeserpidic acid, which may also be obtained frommethyl desoxydeserpidatc by hydrolysis of the carbomethoxy group, forexample with an aqueous-alcoholic solution of sodium hydroxide.

0.5 part by weight of methyl desoxydeserpidate thus obtained issuspended in 4.5 parts by volume of freshly distilled hydrobromic acidhaving a boiling point of 123- 125, and heated at for one and one-halfhours, being stirred by a stream of nitrogen. The material is dissolvedduring the reaction. Finally the reaction mixture is allowed to cool andthen poured onto ice. The fiocculent precipitate is filtered off anddissolved in a minimum of methanol. Addition of ammonia precipitates thefree base. This mixture is added to the filtrate which has also beenmade basic and the whole extracted several times with n-butanol. Thebutanol extract is washed twice with water and then evaporated todryness, thus yielding rauwolscinic acid having the empirical formulaC2OH24O3N2 and the most probable structural formula:

Rauwolscinic acid can also be obtained in a similar manner from theabove described desoxydeserpidic acid.

For the preparation of rauwolscine, the above obtained rauwolscinic acidis dissolved in a minimum of methanol, a little ether is added and themixture is allowed to react with an excess of diazomethane in ether forthree hours, after which the initial precipitate is dissolved. Afterevaporation to dryness the residue is taken up in benzene andchromatographed on alumina (Woelm, neutral, activity II-lll). A mixtureof benzene-acetone (9:1) elutes crystalline material which onre-crystallization melts at 240-242, and which is identical withrauwolsciue (a-yohimbine), having the most probable formula:

CHaOOC- Instead of the above mentioned methyl iodo-desoxydeserpidate,there can also be used methyl bromo-desoxy deserpidate which can beobtained as follows:

0.5 part by weight of p-toluene sulfonyl methyl deserpidate and 0.5 partby weight of lithium bromide are refiuxed overnight in 30 parts byvolume of dry acetonitrile and the reaction mixture worked up in thesame manner as given above for the corresponding iodo compound.Trituration of the residue from the evaporation of the chloroformextract yields crystals which on re-crystallizar tion melt at 179-182"with decomposition. This material represents methylbromo-desoxydeserpidate having the empirical formula C22H2703N2B1' andthe most probable structural formula:

CHaOOC- Br hydrochloric acid in a dropwise manner until the solution isstrongly acidic. It is then extracted with 15 parts by volume of etherand re-extractcd with 3 portions each of 10 parts by volume of ether.The aqueous phase is then made basic with concentrated aqueous ammoniaand extracted with 15 parts by volume of methylene chloride andre-extracted with 3 portions each of 10 parts by volume of methylenechloride. The combined methylene chloride extracts are dried overanhydrous potassium carbonate and concentrated in vacuo to give methyldeserpidate as a pale, yellow solid froth which analyzes for theempirical formula C22H2a04N2. In the same manner, by employing dryethanol or butanol instead of methanol, the corresponding alkyldeserpidates are obtained.

Deserpidine itself can be prepared as follows: 500 parts by weight ofdried, finely ground roots of Rauwolfia canescens are extractedbatch-wise with methanol at its boiling point, using the followingvolumes and times, and filtering each extract while hot: 2,000 parts byvolume, 1 hour; 1,000 parts by volume, 45 minutes; 1,000 parts byvolume, 30 minutes; 1,000 parts by volume, 30 minutes. The extracts arecombined and evaporated in vacuo to 75 parts by volume of thick syrupysolution. After the addition of 75 parts by volume of methanol and 150parts by volume of acetic acid of 15 percent strength with adequatemixing, the solution is extracted with 2 portions each of parts byvolume of hexane. The combined hexane extracts are extracted with 15parts by volume of acetic acid of 15 percent strength. The latterextract is added to the above acetic acid phase which is then extractedwith 3 portions each of 75 parts by volume and 1 portion of 50 parts byvolume of ethylene chloride. The first 3 extracts are combined andwashed with 60 parts by volume of 2 N sodium carbonate solution and thenwith 60 parts by volume of distilled water. These washing solutions aresaved and used for the washing of the 4th and final ethylene chlorideextract. The combined ethylene chloride extracts are dried over sodiumsulfate, filtered and evaporated in vacuo to a constant weight of. atan, frothy solid. 1 part by Weight of this residue is dissolved in 1.5parts by volume of warm methanol and the solution cooled to 5 C. for 18hours, whereby crystallization of a mixture containing principallyreserpine sets in.

0.665 part by weight of the above product is dissolved in 8 parts byvolume of methylene chloride, treated with 0.05 part by weight ofactivated charcoal which is then removed by filtration, using 2 parts byvolume of methylene chloride as a wash. While the methylene chloride isdistilled off it is replaced by 6 parts by volume of methanol. Thedistillation is continued until the methylene chloride is removed and avolume of approximately 2 parts by volume of methanol remains. Afterstanding over night at-5, the crystals of impure reserpine are filteredand washed with three portions each of 0.25 part by volume of coldmethanol. The mother liquor and wash from the above crystals isevaporated in vacuo to a tan solid residue. 0.85 part by weight of thisis dissolved with warming in 2.1 parts by volume of acetone. Needlescrystallize from the warm solution. After standing for 2 hours at roomtemperature, the crystals are filtered, washed with cold acetone, anddried in vacuo at 50 for several hours. 0.236 part by weight of thesecrystals are dissolved in boiling acetone, the solution concentrated toa volume of 1.7 parts by volume, cooled at room temperature, whereuponcrystallization sets in. After standing at room temperature over night,the crystals are filtered, washed with cold acetone, and dried in vacuoat 50 for 5 hours, 0.143 part by weight of these crystals are dissolvedin 0.5 part by volume of warm methanol. The crystals dissolve readilyand from the solution there crystallize rapidly rosettes of tinyprismatic needles. After standing at room temperature over night, thecrystals are filtered and washed with cold methanol. The thus obtaineddeserpidine melts at 228232.

Example 2 0.5 part by weight of methyl bromo-desoxydeserpidate aredissolved in 25 parts by volume of methanol to which have been added0.05 part by weight of sodium hydroxide. After the addition of about 1part by weight of Rancy nickel, the mixture is hydrogenated atatmospheric pressure and room temperature. After approximately 1 mole ofhydrogen has been absorbed, the reaction is stopped, the catalystfiltered off, and the methanolic solution concentrated to a small volumeof about parts by volume. On dilution with water, the base precipitatesand is extracted with chloroform. The extract is washed with water,dried with anhydrous sodium sulfate and the solvent removed. The residueis crystallized from methanol to yield methyl desoxydeserpidateidentical with that described in Example 1.

Example 3 1.5 parts by weight of 3,4,5-trimcthoxy-benzoic acid isdissolved in 17 parts by volume of thionyl chloride and the solutionrefluxed for four hours. The excess of thionyl chloride is removed bydistillation with toluene. The crude acid chloride is then dissolved in5 parts by volume of pyridine, and 05 part by weight of rauwolscinc isadded. The mixture is allowed to stand for four days at roomtemperature. About parts by volume of. water are added gradually and thesolvents then removed by distillation in vacuo. The residue is taken upin chloroform and the solution washed with dilute aqueous ammonia andwater. After drying, the solvent is removed and the residuechromatographed on 18 parts by weight of alumina (Woelm, activity I141!)in benzene solution. The ester is eluted with benzene and isrecrystallized from an acetone-Water mixture. The thus obtained3,4.5-trimethoxy-benzoyl rauwolscine melts at 231-23. It has theempirical formula C31H36N20'l and can he represented by the mostprobable formula:

(BOHs OCH What is claimed is:

l. lS-haiogeno-lS-desoxydeserpidic acid.

2. Acid addition salts of the compound of claim 1.

3. Salts of the compounds of claim 1 with a metal selected from thegroup consisting of alkali and alkaline earth metals.

. 18-bromo-18-desoxydeserpidic acid.

. 18-iodo-18-desoxydeserpidic acid.

. Acid addition salts of the compounds of claim 7.

. Lower alkyl l8-halogeno-l8-desoxydeserpidates.

. Methyl 1S-bromo-l8-desoxydeserpidate.

. Methyl 18-iodo-1S-desoxydeserpidate.

10. l8-desoxydeserpidic acid.

1 1. Acid addition salts of the compound of claim 10.

J2. Salts of the compound of claim 10 with a metal selected from thegroup consisting of alkali and alkaline earth metals.

13. Acid addition salts of the compounds of claim l4.

14. Lower alkyl l8desoxydeserpidates.

15. Methyl lS-desoxydeserpidate.

16. A process for the preparation of rauwolscinic acid comprisingtreating methyl O-p-toluene sulfonyl-deserpidate with sodium iodide soas to replace the O-p-toluene sulfonyloxy group by iodine, treating theobtained methyl 18-iodo-l8-desoxydeserpidate with zinc in glacial aceticacid so as to remove the iodine, and hydrolyzing the obtained methyllddesoxydeserpidate with hydrobromic acid so as to obtain rauwolscinicacid.

17. A process for the preparation of rauwolscinic acid which comprisestreating a lower alkyl O-p-toluene sulfonyl-deserpidate with an alkalimetal halide, treating the resulting lower alkyll8-halogeno-lS-desoxydeserpidate with a reducing agent selected from thegroup consisting of zinc in the presence of an acid and hydrogen in thepresence of Raney nickel, to replace the halogen atom by hydrogen, andtreating the lower alkyl l8-desoxydeserpidate thus obtained withconcentrated aqueous hydrohalic acid so as to produce rauwolscinic acid.

18. A process for the preparation of rauwolscinic acid which comprisestreating a lower alkyl O-p-toluene sulfonyl-deserpidate with an alkalimetal halide, treating the resulting lower alkyll8-halogeno-18-desoxydeserpidate with an alkaline hydrolysis agent,treating the resulting l8-halogeno-l8-desoxydeserpidic acid with areductive agent selected from the group consisting of zinc in thepresence of an acid and hydrogen in the presence of Raney nickel, toreplace the halogen atom by hydrogen, and treating the18-desoxydeserpidic acid thus obtained with concentrated aqueoushydrohalic acid so as to produce rauwolscinic acid.

References Cited in the file of this patent UNITED STATES PATENTS684,650 Spiegel Oct. 15, 1901 716,776 Spiegel Dec. 23, 1902 996,274Muller June 27, 1911 OTHER REFERENCES Beil, vol. XXV, 2nd supplement,pages 200-212.

Janat et al.: Bull. Soc. Chem., vol. 16 (1949), pages 5095l5.

Chatterjee: Journal Indian Chem. Soc., vol. 28, No. 1 (1951), pages29-33.

1. 18-HALOGENO- 18-DESOXYDESERPIDIC ACID.
 16. A PROCESS FOR THEPREPATATION OF RAUWOLSCINIC ACID COMPRISING TREATING METHYL O-P-TOLUENESULFONYL-DESERPIDATE WITH SODIUM IODIDE SO AS TO REPLACE THE O-P-TOLUENESULFONYLOXY GROUP BY IODINE, TREATING THE OBTAINED METHYL18-IODO-18-DESOXYDESERPIDATE WITH ZINC IN GLACIAL ACETIC ACID SO AS TOREMOVE THE IODINE, AND HYDROLYZING THE OBTAINED METHYL18-DESOXYDESERPIDATE WITH HYDROBROMIC ACID SO AS TO OBTAIN RAUWOLSCINICACID.